The increased proliferation rate and progression of various cancers can be directly linked to defects in apoptotic signaling cascades. Akt is a central protein in the PI3K pathway that confers resistance to apoptosis through inactivation of intracellular substrates. Hyperactivation of Akt is essential in the initiation and maintenance of over 50% of all human tumors. The most common include breast, ovarian, pancreatic, and gastric cancers, as well as the particularly aggressive hormone-refractory prostate cancers. Inhibition of the kinase activity of Akt is a clinically validated strategy for the treatment of thse malignancies. However, most efforts directed toward this end focus on agents that displace endogenous ATP from the Akt binding pocket-a strategy that often yields promiscuous lead compounds that inhibit other homologous kinases. In contrast, our laboratory is engaged in the development of Akt inhibitors that specifically target the protein substrate-binding cleft adjacent to the ATP site. The rationale behind this approach is the notion that the protein-protein interaction (PPI) region of Akt harbors a far more discerning topology relative to other binding sites. Recent X- ray co-crystal structures of Akt bound to truncated sections of its endogenous substrate GSK3b have informed the design of various peptide lead structures. Although targeting the PPI domain of Akt is presumably more difficult due to the extensive interaction region, a number of compelling factors have prompted us to pursue a PPI-targeting strategy, including (1) the discovery, in our lab, of a potent substrate mimetic lead inhibitor with reduced peptide character, (2) a structural rationale for refinements based on X-ray crystallography, (3) extensive clinical validation for targeting Akt, and (4) the lack of an FDA-approved Akt inhibitor for the treatment of cancer. Here, we propose the structure-based design and synthesis of a focused library of analogs based on our lead inhibitor, and their biological evaluation in vitro an in whole cell assays. The objective of this project is to provide the first non-peptide substrate mimetic inhibitors capable of selectively targeting Akt-dependant tumor cells. Our longer-term goals are to use a PPI approach to develop clinical candidates with more favorable therapeutic profiles and to apply this strategy to the inhibition of other oncogenic kinases.